Effective mechanical potential of cell-cell interaction explains three-dimensional morphologies during early embryogenesis.

Mechanical forces are critical for the emergence of diverse three-dimensional morphologies of multicellular systems. However, it remains unclear what kind of mechanical parameters at cellular level substantially contribute to tissue morphologies. This is largely due to technical limitations of live measurements of cellular forces. Here we developed a framework for inferring and modeling mechanical forces of cell-cell interactions. First, by analogy to coarse-grained models in molecular and colloidal sciences, we approximated cells as particles, where mean forces (i.e. effective forces) of pairwise cell-cell interactions are considered. Then, the forces were statistically inferred by fitting the mathematical model to cell tracking data. This method was validated by using synthetic cell tracking data resembling various in vivo situations. Application of our method to the cells in the early embryos of mice and the nematode Caenorhabditis elegans revealed that cell-cell interaction forces can be written as a pairwise potential energy in a manner dependent on cell-cell distances. Importantly, the profiles of the pairwise potentials were quantitatively different among species and embryonic stages, and the quantitative differences correctly described the differences of their morphological features such as spherical vs. distorted cell aggregates, and tightly vs. non-tightly assembled aggregates. We conclude that the effective pairwise potential of cell-cell interactions is a live measurable parameter whose quantitative differences can be a parameter describing three-dimensional tissue morphologies.

Analysis of adverse events related to extracorporeal membrane oxygenation from a nationwide database of patient-safety accidents in Japan.

Although adverse events related to extracorporeal membrane oxygenation have been reported, epidemiological data on life-threatening events are insufficient to study the causes of such adverse events. Data from the Japan Council for Quality Health Care database were retrospectively analyzed. The adverse events extracted from this national database included events associated with extracorporeal membrane oxygenation reported between January 2010 and December 2021. We identified 178 adverse events related to extracorporeal membrane oxygenation. At least 41 (23%) and 47 (26%) accidents resulted in death and residual disability, respectively. The most common adverse events were cannula malposition (28%), decannulation (19%), and bleeding (15%). Among patients with cannula malposition, 38% did not undergo fluoroscopy-guided or ultrasound-guided cannulation, 54% required surgical treatment, and 18% required trans-arterial embolization. In this epidemiological study in Japan, 23% of the adverse events related to extracorporeal membrane oxygenation had fatal outcomes. Our findings suggest that a training system for cannulation techniques may be needed, and hospitals offering extracorporeal membrane oxygenation should perform emergency surgeries.

An ImageJ-based tool for three-dimensional registration between different types of microscopic images.

Three-dimensional (3D) registration (i.e., alignment) between two microscopic images is very helpful to study tissues that do not adhere to substrates, such as mouse embryos and organoids, which are often 3D rotated during imaging. However, there is no 3D registration tool easily accessible for experimental biologists. Here we developed an ImageJ-based tool which allows for 3D registration accompanied with both quantitative evaluation of the accuracy and reconstruction of 3D rotated images. In this tool, several landmarks are manually provided in two images to be aligned, and 3D rotation is computed so that the distances between the paired landmarks from the two images are minimized. By simultaneously providing multiple points (e.g., all nuclei in the regions of interest) other than the landmarks in the two images, the correspondence of each point between the two images, i.e., to which nucleus in one image a certain nucleus in another image corresponds, is quantitatively explored. Furthermore, 3D rotation is applied to one of the two images, resulting in reconstruction of 3D rotated images. We demonstrated that this tool successfully achieved 3D registration and reconstruction of images in mouse pre- and post-implantation embryos, where one image was obtained during live imaging and another image was obtained from fixed embryos after live imaging. This approach provides a versatile tool applicable for various tissues and species.

Determinant factors behind changes in health-seeking behaviour before and after implementation of universal health coverage in Indonesia.

BACKGROUND: The health insurance system in Indonesia was transformed in 2014 to achieve universal health coverage (UHC). The effective implementation of essential primary health services through UHC has resulted in efficient healthcare utilisation, which is reflected in the health-seeking behaviour of the community. Our study aimed to examine the changes in health-seeking behaviour before and after the implementation of UHC in Indonesia and to identify what factors determine these changes. METHODS: We conducted a retrospective cohort study using the recall method and data collected through questionnaire-based interviews in Bandung, Indonesia. We used a two-step sampling technique-randomised sampling and purposive sampling, and a total of 579 respondents with acute or chronic episodes were recruited. [Formula: see text] tests were used to identify the association between factors. Difference in difference model and a logistic regression model for binary outcomes were used to estimate the effect of the implementation of UHC on the health-seeking behaviour. RESULTS: Utilisation of public health facilities increased significantly after implementation of UHC, from 34.9% to 65.4% among the respondents with acute episodes and 33.7% to 65.8% among those with chronic episodes. The odds of respondents going to health facilities when they developed an acute episode increased after the implementation of UHC (OR = 1.22, p = 0.05; AOR = 1.42, p < 0.001). For respondents experiencing chronic episodes, the implementation of UHC increased the odds ratio (OR = 1.74, p < 0.001; AOR = 1.64, p < 0.001) that they would use health facilities. Five years after the implementation of UHC, we still found respondents who did not have health insurance (26 and 19 respondents among those with acute episode and chronic episode, respectively). CONCLUSIONS: The effect of the implementation of UHC seemed greater for those experiencing chronic episodes than for those with an acute episode. Although the implementation of UHC has improved utilisation of public health facilities, the presence of people who are not covered by health insurance is a potential problem that could threaten future improvements in healthcare access and utilisation.

How Worries about Interpersonal Relationships, Academic Performance, Family Support, and Classmate Social Capital Influence Suicidal Ideation among Adolescents in Japan.

Suicide is an important public health issue for adolescents. To investigate the risk and protective factors for adolescent suicide, a cross-sectional questionnaire-based survey was conducted at a junior high school (n = 379) in Japan in 2018. After obtaining survey data, we conducted univariate and logistic regression analyses to test for associations between suicidal ideation and several factors, including worries (i.e., about school life, interpersonal relationships at school, family life, interpersonal relationships at home, and academic performance), perceived support from school staff and family members, and social capital. In this context, the existence of trustful relationships between classmates was used as indicators of social capital. The results showed that the prevalence of suicidal ideation was 10.5%. The risk of suicidal ideation was increased by worries about 1) interpersonal relationships at school, 2) interpersonal relationships at home, and 3) academic performance, but was decreased by social support from family members and trusting relationships. Further, the rate of suicidal ideation was higher among students who expressed all these three worries when compared to those who expressed two or fewer worries. In addition, looking at students who expressed all these three worries simultaneously, the rate of suicidal ideation was higher among those with lower levels of support from family members and fewer trustful relationships. Our results suggest that the prevention of adolescent suicide should include strategies for reducing worries about interpersonal relationships at school/home and academic performance while finding ways to enhance family support and classmate social capital.

Decreased numbers of gastric, colorectal, lung, and breast cancer surgeries performed in 17 cancer-designated hospitals in Gunma Prefecture of Japan during the COVID-19 pandemic.

PURPOSE: This study aims to clarify the influence of the COVID-19 pandemic on cancer surgery in Gunma Prefecture. METHODS: A total of 9839 cases (1406 gastric cancer, 3569 colorectal cancer, 1614 lung cancer, and 3250 breast cancer) from 17 hospitals in Gunma Prefecture were investigated. We compared the number of surgical cases, proportion of cases found by screening, and cStage at the time of the first visit by month in 2020 and 2021 with those in 2019. RESULTS: The rate of decline in cancer surgery was 8.9% in 2020 compared with 2019 (p = 0.0052). Compared with the same month of 2019, in some months of 2020 and 2021, significant decreases were observed in the number of surgeries for gastric and colorectal cancer, the percentage of surgical cases detected by screening in all four cancers, and the proportion of cancers with a relatively early cStage in gastric and breast cancer. CONCLUSIONS: The number of surgical cases of the four cancer types detected by cancer screening decreased in Gunma Prefecture owing to the influence of the COVID-19 pandemic. Furthermore, for some cancer types, the number of operations performed in patients with early-stage cancer is also decreased.

Biosorption of different gadolinium (Gd) complexes from water by Eichhornia crassipes (water hyacinth).

Many studies have demonstrated the Eichhornia crassipes (water hyacinth) potency in removing heavy metals, but the plant's potential for sorption of gadolinium (Gd) has not yet been investigated. In this study, water hyacinth was grown in a glass container for 30 days with either GdCl3 or Gd-based contrast agent (GBCA; gadoterate) with water obtained from the Tone River. On the day 30, the Gd concentration in both the water and the plants was measured by mass spectrometry (ICP-MS). After 30 days, 98.5% of GdCl3 in the water had been absorbed by the roots, and 3.5% of Gd was transferred to the leaves. On the other hand, the water hyacinth roots absorbed only 12% of the gadoterate. When exposed to 5 mg/L of GdCl3, the roots of water hyacinth may effectively remove Gd ions in the aquatic environment, with no visible effect on the general health of the plant. However, the water hyacinth roots did not absorb GBCA. This may result in higher accumulation of Gd in the aqueous environment. The GBCA may be broken down by environmental factors and negatively affect the marine ecosystem.

This study highlights the potential capability of water hyacinths in reducing the increasing gadolinium in the environment, which may be of value in optimizing the phytoremediation of medical waste.

Repetitive short-pulsed illumination efficiently activates photoactivatable-Cre as continuous illumination in embryonic stem cells and pre-implantation embryos of transgenic mouse.

The Cre-loxP system has been widely used for specific DNA recombination which induces gene inactivation or expression. Recently, photoactivatable-Cre (PA-Cre) proteins have been developed as a tool for spatiotemporal control of the enzymatic activity of Cre recombinase. Here, we generated transgenic mice bearing a PA-Cre gene and systematically investigated the conditions of photoactivation for the PA-Cre in embryonic stem cells (ESCs) derived from the transgenic mice and in a simple mathematical model. Cre-mediated DNA recombination was induced in 16% of the PA-Cre ESCs by 6 hr continuous illumination. We show that repetitive pulsed illumination efficiently induced DNA recombination with low light energy as efficient as continuous illumination in the ESCs (96 ± 15% of continuous illumination when pulse cycle was 2 s), which was also supported by a minimal mathematical model. DNA recombination by the PA-Cre was also successfully induced in the transgenic mouse pre-implantation embryos under the developed conditions. These results suggest that strategies based on repetitive pulsed illumination are efficient for the activation of photoactivatable Cre and, possibly other photo-switchable proteins.

The effect of denosumab in breast cancer patients receiving adjuvant aromatase inhibitors: 36-month results.

INTRODUCTION: Aromatase inhibitor (AI)-associated bone loss increases the risk of bone fracture and reduces patients' quality of life, making it a critical issue worldwide. We conducted a prospective non-randomized clinical trial (UMIN-CTR, UMIN 000016173) to assess the effect of denosumab on bone loss in patients treated with adjuvant AI and have previously reported the results at 12 and 24 months. This study aimed to present the results at 36 months of treatment with denosumab for osteopenia in breast cancer patients who were undergoing treatment with adjuvant AI; 36 months is the longest denosumab treatment period reported so far. MATERIALS AND METHODS: Patients received 60-mg denosumab subcutaneously every 6 months. Daily supplements containing 500-mg elemental calcium and at least 400 international units of vitamin D were highly recommended throughout the study period. The levels of bone mineral density (BMD) and bone turnover markers, serum tartrate-resistant acid phosphatase isoform 5b, and bone alkaline phosphatase were determined at baseline and 6, 12, 18, 24, and 36 months. RESULTS: At 36 months, the bone mineral density of the lumbar spine, right femoral neck, and left femoral neck were found to increase by 8.8% (95% confidence interval CI 7.6-10.1), 4.3% (95% CI 3.0-5.5), and 3.1% (95% CI 2.1-4.1), respectively. No non-traumatic clinical fractures occurred in patients receiving AI and denosumab. CONCLUSION: Twice-yearly administration of denosumab to the breast cancer patients treated with adjuvant AI, regardless of the skeletal site, resulted in consistent increases in BMD without severe adverse events at 36 months.

Distinct intracellular Ca2+ dynamics regulate apical constriction and differentially contribute to neural tube closure.

Early in the development of the central nervous system, progenitor cells undergo a shape change, called apical constriction, that triggers the neural plate to form a tubular structure. How apical constriction in the neural plate is controlled and how it contributes to tissue morphogenesis are not fully understood. In this study, we show that intracellular calcium ions (Ca2+) are required for Xenopus neural tube formation and that there are two types of Ca2+-concentration changes, a single-cell and a multicellular wave-like fluctuation, in the developing neural plate. Quantitative imaging analyses revealed that transient increases in Ca2+ concentration induced cortical F-actin remodeling, apical constriction and accelerations of the closing movement of the neural plate. We also show that extracellular ATP and N-cadherin (cdh2) participate in the Ca2+-induced apical constriction. Furthermore, our mathematical model suggests that the effect of Ca2+ fluctuations on tissue morphogenesis is independent of fluctuation frequency and that fluctuations affecting individual cells are more efficient than those at the multicellular level. We propose that distinct Ca2+ signaling patterns differentially modulate apical constriction for efficient epithelial folding and that this mechanism has a broad range of physiological outcomes.

Isotropic expansion of external environment induces tissue elongation and collective cell alignment.

Cell movement is crucial for morphogenesis in multicellular organisms. Growing embryos or tissues often expand isotropically, i.e., uniformly, in all dimensions. On the surfaces of these expanding environments, which we call "fields," cells are subjected to frictional forces and move passively in response. However, the potential roles of isotropically expanding fields in morphogenetic events have not been investigated well. Our previous mathematical simulations showed that a tissue was elongated on an isotropically expanding field (Imuta et al., 2014). However, the underlying mechanism remains unclarified, and how cells behave during tissue elongation was not investigated. In this study, we mathematically analyzed the effect of isotropically expanding fields using a vertex model, a standard type of multi-cellular model. We found that cells located on fields were elongated along a similar direction each other and exhibited a columnar configuration with nearly single-cell width. Simultaneously, it was confirmed that the cell clusters were also elongated, even though field expansion was absolutely isotropic. We then investigated the mechanism underlying these counterintuitive phenomena. In particular, we asked whether the dynamics of elongation was predominantly determined by the properties of the field, the cell cluster, or both. Theoretical analyses involving simplification of the model revealed that cell clusters have an intrinsic ability to asymmetrically deform, leading to their elongation. Importantly, this ability is effective only under the non-equilibrium conditions provided by field expansion. This may explain the elongation of the notochord, located on the surface of the growing mouse embryo. We established the mechanism underlying tissue elongation induced by isotropically expanding external environments, and its involvement in collective cell alignment with cell elongation, providing key insight into morphogenesis involving multiple adjacent tissues.

Determinants of life expectancy and clustering of provinces to improve life expectancy: an ecological study in Indonesia.

BACKGROUND: Life expectancy acts as a population measure of the performance of healthcare systems. Regional disparities on life expectancy in Indonesia has been persisted and become a public health policy challenge. A systematic clustering of provinces can be a valuable alternative for organizing cooperation that aimed to increase life expectancy and reduce disparities. This study aimed to identify determinants of life expectancy and designate clusters of Indonesian provinces with similar characteristics. This approach can be useful in generating alternative cooperation strategies to improve life expectancy. METHODS: We carefully selected variables that have been shown to impact life expectancy and gathered 2015 data from Indonesia's Ministry of Health. All 34 Indonesian provinces were included as analysis units. We performed structural equation modeling (SEM) to select domains that needed to work on from theoretical models. Based on SEM results, we performed cluster analysis to arrange cooperation groups. RESULTS: Life expectancy showed correlations with mean years of schooling, expenditure per capita, health workforce, healthcare facilities, and environment. Expenditure per capita also was the strongest of all constructs. Based on SEM results, we performed cluster analysis to arrange cooperation groups of total 34 provinces and generated five clusters of provinces. CONCLUSIONS: Enhancing the economy is the most effective approach for improving life expectancy and other constructs. These clusters can build cooperation that is new, within, and across clusters. These results may be useful in formulating cooperation strategies aimed at increasing life expectancy.

Clinical significance of serum PSA in breast cancer patients.

BACKGROUND: Recent preclinical data suggest that androgen receptor (AR) signaling plays a significant role in subsets of breast cancer. Clinical trials testing AR-targeting therapies in breast cancer have been conducted. Assessment of AR-signal in breast cancer tissue maybe useful for treatment selections. Prostate specific antigen (PSA) is the product of an androgen-responsive gene. Serum PSA (sPSA) can be detected in women by a highly sensitive assay although the concentration is much lower than that observed in males. We investigated if sPSA reflects tumor biology, including AR signaling in breast cancer patients. METHODS: In this study, 132 healthy controls and 144 breast cancer patients were enrolled. sPSA was evaluated by the chemiluminescent enzyme immunoassay (CLEIA) method. Correlations between sPSA and the various clinicopathological factors were analyzed. RESULTS: In post-menopausal state, sPSA detection rate was significantly higher in breast cancer patients compared with controls (27.4% vs 11.3%: p = 0.0090), but not in the whole cohort (29.2% vs 25.8%: p = 0.5265) or pre-menopausal subgroup (37.0% vs 42.6%: p = 0.6231). In post-menopausal breast cancer cases, higher sPSA value was associated with clinic-pathological factors including the expression of AR protein in primary legion. In a correlation analysis of quantitative data limited to post-menopausal metastatic breast cancer (MBC), sPSA was positively, albeit weakly correlated with clinic-pathological features including serum testosterone levels and AR positivity. CONCLUSIONS: Our data suggest that sPSA may reflect tumor biological properties including AR activity in post-menopausal breast cancer.

Effects of denosumab on bone mineral density in Japanese women with osteoporosis treated with aromatase inhibitors for breast cancer.

Adjuvant aromatase inhibitor (AI) therapy, for hormone receptor-positive breast cancer, in postmenopausal women is associated with bone loss, leading to an increased risk of fractures. Denosumab, an antibody raised against the receptor activator of nuclear factor-κB ligand, has been proven to protect against AI-induced bone loss. Hence, we aimed to determine whether denosumab is effective in postmenopausal Japanese women with osteoporosis, treated with AI. We prospectively evaluated the bone mineral density (BMD) in the lumbar spine and the bilateral femoral neck in 102 postmenopausal women with clinical hormone receptor-positive breast cancer, stages I-IIIA, during a postoperative period of 12 months. The other inclusion criteria for this study were: women that should receive AIs as adjuvant therapy and those with evidence of osteoporosis (lumbar spine or bilateral femoral neck BMD, equivalent to T-score classification of ≤ - 2.5) upon enrollment. The patients received supplemental calcium, vitamin D, and 60 mg of subcutaneous denosumab every 6 months. The BMD of the lumber spine increased by 4.9 and 6.6% at 6 and 12 months, respectively. An increase in BMD was observed at the femoral neck, bilaterally. Hypocalcemia ≥ grade 2, osteonecrosis of the jaw, and non-traumatic clinical fracture were not observed in this study. Our findings revealed that biannual treatment with denosumab is associated with a great increase of BMD in Japanese women receiving adjuvant AI therapy, irrespective of their previous history of AI therapy.

Predictive factors for the efficacy of denosumab in postmenopausal Japanese women with non-metastatic breast cancer receiving adjuvant aromatase inhibitors: a combined analysis of two prospective clinical trials.

Aromatase inhibitors (AIs) are the gold standard therapy for breast cancer in postmenopausal women. AI suppresses the conversion of androgens to estrogens; however, this results in osteopenia, osteoporosis, and bone fracture, thus reducing the patient's quality of life. The use of adjuvant denosumab reduces the risk of clinical fractures in postmenopausal patients with breast cancer receiving AI. However, the efficacy of denosumab in the treatment of AI-associated bone loss has not been prospectively evaluated in Japan. In this study, we aimed to investigate the predictive factors for the efficacy of denosumab in postmenopausal patients with breast cancer treated with AI by analyzing the results of two prospective trials. The patients received 60 mg denosumab subcutaneously every 6 months. The primary endpoint was percentage change in lumbar spine bone mineral density (BMD) from baseline to month 12 in lumbar spine. Post hoc analysis and T tests were performed. A total of 205 patients were enrolled. At 12 and 24 months, the lumbar spine BMD increased by 5.6% [95% confidence interval (CI) 4.9-6.3] and 8.3% (95% CI 7.5-9.1), respectively. Subgroup analysis was conducted according to the time of AI therapy initiation, type of AI therapy, age, time since menopause, baseline body mass index, and BMD. The results showed that baseline lumbar and left femoral BMD was significantly associated with a percentage change in these sites, respectively. In addition, baseline left femoral BMD was also associated with a change in lumbar BMD. In conclusion, the baseline BMD in the lumbar spine was a predictive indicator for the efficacy of denosumab in this site and the baseline BMD in left femoral neck was a predictive indicator in lumbar spine and left femur.

Association between Depressive State and Lifestyle Factors among Residents in a Rural Area in Japan: A Cross-Sectional Study.

For the prevention of suicides, the early detection of depression symptoms and the implementation of suicide prevention measures based on the local community's conditions are critical. In rural or remote communities with poor access to urban areas, the medical care is often insufficient. We conducted the present study to investigate the relationship between depressive state and social-environmental factors in a depopulated inland rural area in central Japan, where the suicide rate is high and specialized psychiatric care is not available. Using a correspondence analysis, logistic regression analysis, and structural equation modeling (SEM), we examined the questionnaire responses of 912 residents (average 60.5 years old). Total Health Index-Depression (THI-D) scale scores were used to measure depressive state. The lifestyle-related factor with the strongest link to depressive state was 'concerns about interpersonal relationships' (OR = 2.7, 95% CI: 2.06-3.53, p < 0.0001), whereas financial concerns, number of friends, exercise habits, and perceived amount of sleep were also useful for predicting depressive state. The SEM showed that one's job and private life, particularly concerns about interpersonal relationships, are correlated with higher THI-D scores. Thus, social and lifestyle factors (e.g., concerns about interpersonal relationships and financial situation) can be used to predict depressive state in a depopulated rural area, and the newly revealed order in which depressive symptoms manifest is important. Our findings can be used to advance assessments of depressive symptoms and will be useful for mental health and suicide prevention.

Mongolian Health Sector Strategic Master Plan (2006-2015): A foundation for achieving universal health coverage.

Nearly half of the countries in the world are in the process of reforming and strengthening their health care systems. More recently, even low-income and middle-income countries such as Mongolia have focused increasing attention on achieving universal health coverage (UHC). At this critical point, it is necessary to track recent progress and adjust health care strategies and planning. Therefore, this study analyzed changes in the health sector toward achieving UHC based on relevant literature, government documents, and framework analysis. We also investigated how basic principles of UHC were incorporated and reflected in Mongolia's Health Sector Strategic Master Plan. This study clarified the achievements of and challenges facing the health sector that remain or emerged during the plan's implementation over the last decade. Furthermore, all of the reviewed Master Plan strategies were underpinned by basic principles of UHC. However, strategies set out in the next Master Plan will require adjustments and innovative measures to respond to current challenges. This study may be used as a reference for other developing countries to track UHC achievements and serve as a guide to establishing a nation-wide strategic plan.

[A Case of Stromal Sarcoma of the Breast Showing Rapid Increase].

An 83-year-old woman visited our hospital with a mass on her right breast mass. Breast ultrasonography revealed a tumorous lesion approximately 30mm in diameter in the right E region. Fibrous tumor was suspected from core needle biopsy. Since surgery for definite diagnosis was not desired, she was followed. Seven months after the first visit, skin redness, pain, and rapid increase in tumor size was consciously recognized, which prompted a reconsultation. The tumor diameter rapidly increased to 74 mm, and a total right mastectomy was performed as a semi-emergency procedure. Necrotic and hemorrhagic lesions were mixed in a mottled state in the cleaved surface of the excised specimen, and the pathological diagnosis was stromal sarcoma mainly comprising of fibrosarcoma components. Stromal sarcoma of the breast lacks the epithelial component of a malignant phyllodes tumor, and effective systemic therapy has not been established; therefore, cases with local recurrence or distant metastasis result in poor prognosis. Since we encountered a case of stromal sarcoma of the breast that showed a rapid increase after several months, we will provide a report with some literature consideration.

Effect of denosumab administration on low bone mineral density (T-score -1.0 to -2.5) in postmenopausal Japanese women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer.

Although adjuvant aromatase inhibitor (AI) therapy is widely used in postmenopausal women with hormone receptor-positive breast cancer, it is known to be associated with bone loss and increased fracture risk. Denosumab, a fully human monoclonal antibody against the receptor activator of nuclear factor-κB ligand, has been shown to protect against AI-induced bone loss. However, the efficacy of denosumab in the treatment of AI-associated bone loss has not been prospectively evaluated in Japan. We prospectively monitored bone mineral density (BMD) of the lumbar spine and bilateral femoral necks in 100 postmenopausal women with hormone receptor-positive postoperative breast cancer of clinical stage I-IIIA in whom treatment with AI as adjuvant endocrine therapy was planned or had been ongoing. Study participants received supplemental calcium and vitamin D every day and denosumab (60 mg) subcutaneously every 6 months. At enrollment, patients were required to have evidence of low bone mass without meeting the criteria for osteoporosis. The primary endpoint was percentage change from baseline in lumbar spine BMD at month 12. At 6 and 12 months, lumbar spine BMD increased by 3.3 and 4.7%, respectively. BMD of the femoral necks also increased. Hypocalcemia of grade ≥2, osteonecrosis of the jaw, and non-traumatic clinical fracture did not occur. In conclusion, semi-annual treatment with denosumab was associated with increased BMD in Japanese women receiving adjuvant AI therapy, regardless of prior AI treatment.

Distribution trends of Indonesia's health care resources in the decentralization era.

Indonesia has been decentralized since 2001, and we evaluated the distribution trends of physicians, puskesmas (community health centers), hospitals, and hospital beds in 34 provinces in Indonesia for 2000 to 2014. Inequality index of Gini showed improvement of the distribution of physicians and decreased from 0.38 to 0.29. The indices in distributions of hospitals and hospital beds also decreased from 0.26 to 0.17 and from 0.25 to 0.18, respectively. However, the index in the distribution of puskesmas increased from 0.19 to 0.28. We also investigated the legislative transitions of the laws concerning health resources and found the strong affects of compulsory work laws for physicians and the increment of health budget. In the decentralization era, the local governments have some political autonomy for the development of health resources; however, the national government should monitor the nationwide distribution of health resources and advice necessary recommendations to the local governments.